ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis

We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.     

Magma heating by decompression-driven crystallization beneath andesite volcanoes

Explosive volcanic eruptions are driven by exsolution of H2O-rich vapour from silicic magma. Eruption dynamics involve a complex interplay between nucleation and growth of vapour bubbles and crystallization, generating highly nonlinear variation in the physical properties of magma as it ascends beneath a volcano. This makes explosive volcanism difficult to model and, ultimately, to predict. A key unknown is the temperature variation in magma rising through the sub-volcanic system, as it loses gas and crystallizes en route. Thermodynamic modelling of magma that degasses, but does not crystallize, indicates that both cooling and heating are possible. Hitherto it has not been possible to evaluate such alternatives because of the difficulty of tracking temperature variations in moving magma several kilometres below the surface. Here we extend recent work on glassy melt inclusions trapped in plagioclase crystals to develop a method for tracking pressure-temperature-crystallinity paths in magma beneath two active andesite volcanoes. We use dissolved H2O in melt inclusions to constrain the pressure of H2O at the time an inclusion became sealed, incompatible trace element concentrations to calculate the corresponding magma crystallinity and plagioclase-melt geothermometry to determine the temperature. These data are allied to ilmenite-magnetite geothermometry to show that the temperature of ascending magma increases by up to 100 degrees C, owing to the release of latent heat of crystallization. This heating can account for several common textural features of andesitic magmas, which might otherwise be erroneously attributed to pre-eruptive magma mixing.     

The effect of Emetine on macromolecular synthesis in synchronizedTetrahymena pyriformis

Zusammenfassung Emetin hemmt die synchronisierte Teilung vonTetrahymena pyriformis, verhindert die rasche Aufnahme von Aminosäuren und verursacht offenbar eine Zellteilungshemmung.

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This work was supported in part by grants from the Hawaii Heart Association and the Julius and Dorothy Fried Foundation.     

Accessibility of a critical prion protein region involved in strain recognition and its implications for the early detection of prions

Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated PrP27 – 30 detectable by the 3F4 antibody against human PrP109 – 112. We recently identified a new PK-resistant PrP species, designated PrP^*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 – 108 but not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP^*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic mutant PrP accumulate not only PrP^*20 but also a small amount of 3F4-detected PK-resistant PrP27 – 30. Remarkably, during the course of human prion disease, a transition from an increase in 1E4-detected PrP^*20 to the occurrence of the 3F4-detected PrP27 – 30 was observed. Our study suggests that an increase in the level of PrP^*20 characterizes the early stages of prion diseases. Received 17 October 2007; received after revision 5 December 2007; accepted 14 December 2007     

Stage-specific sensitivity to p53 restoration during lung cancer progression

Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.     

Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.